Handbook of clinical drug data - part 7 ppt

Lipids Unopposed oral estrogens reduce LDL and increase HDL by Progesterone antagonizes beneficial estrogen lipid effects less than 10–15%; however, estrogens can increase triglyceride l

ESTROGENS COMPARISON CHART

EQUIPOTENT PHYSIOLOGIC

STEROIDAL AGENTS

Conjugated Estrogens Tab 0.3, 0.625, 0.9, 1.25, 2.5 mg 0.625 mg Mixture of 50–65% sodium estrone sulfate, 20–35% equilin

Esterified Estrogens Tab 0.3, 0.625, 1.25, 2.5 mg 0.625 mg Similar to conjugated estrogens Mixture of 75–85% sodium

Various

Estradiol, Micronized Tab 0.5, 1, 1.5, 2 mg 1 mg Moderate cost; some nausea with oral; estradiol is the major

Vag Ring 2 mg.

Estradiol SR Patch 25, 37.5, 50, 75, 50 µg/day Estraderm contains alcohol; Climara and Vivelle do not contain

EQUIPOTENT PHYSIOLOGIC

Estradiol Valerate Inj (in oil) 10, 20, 40 mg/mL 1 mg Pain at injection site; variable onset with a duration of

Various

Ethinyl Estradiol Tab 0.02, 0.05, 0.5 mg 5 µg Not recommended for estrogen replacement because of its

Feminone

Ogen 5 mg = 6 mg estropipate.

NONSTEROIDAL AGENTSESTROGENS COMPARISON CHART (continued)

Various

a Potency of estrogens: estradiol > estrone Potency is based on the effects on the liver.

bSee monographs or product information for exact dosage regimens for various uses.

RISKS/BENEFITS CLINICAL INFORMATION COMMENTS

Cancer, Breast Controversial; no association with <5 yr duration of use to Addition of progestin does not reduce risk Regular mammography is

relative risk of 1.25–1.45 among current users with >5 yr recommended Consider limiting duration of treatment to <5 yr if duration of use; highest risk of 1.7 reported among long- risks of cancer outweigh cardioprotective benefits.

term users >60 yr No risk found in past users, regardless

of duration of use Two meta-analyses show minimal risk with >15 yr of use.

Cancer, Colon A 46% decrease in colon cancer risk; no effect on rectal cancer In slender women, risk is reduced by up to 75%.

Cancer, Relative risk of 8.2 with unopposed estrogen use; risk increases Relative risk of 1 with the concurrent addition of a minimum of 10–14

Endometrial with higher dosage and duration >5 yr; 34% risk after 3 yr; days of progestin No increased risk of estrogen hyperplasia or need

20% lifetime probability of needing a hysterectomy with un- for hysterectomy with concurrent progestin therapy.

opposed estrogen therapy.

Cardiovascular Three meta-analyses and a cohort study suggest a 40–50% re- Combination with progestin may be protective, but data are insufficient.

Disease duction in the risk of coronary and fatal heart disease with May be related to estrogen’s effects on lipids or direct effect of

re-unopposed estrogens; benefits may be greater in those with laxing blood vessel walls.

heart disease and >15 yr duration of use Decreased lifetime probability of developing coronary artery disease Hormone replacement for ≥1 yr associated with a 52% decreased risk

of peripheral arterial disease Unknown protection against stroke.

Hypertension Estrogens can reduce BP Hormone replacement is not contraindicated in hypertension.

Lipids Unopposed oral estrogens reduce LDL and increase HDL by Progesterone antagonizes beneficial estrogen lipid effects less than

10–15%; however, estrogens can increase triglyceride levels medroxyprogesterone Most favorable effects on lipids occur with

estrogen alone Nonoral estrogens (eg, patch, vaginal) produce less HDL beneficial effects.

(continued )

RISKS/BENEFITS CLINICAL INFORMATION COMMENTS

Gallbladder Estrogen treatment is associated with a 2.1 relative risk (RR) Mortality unaffected; may require cholecystectomy.

Disease RR of 2.6 with >10 yr of use; RR of 2.4 for users of 1.25

mg or more of conjugated/estrified estrogen.

Osteoporosis Inhibits bone resorption and prevents bone loss; 15–50% increase Alendronate (Fosamax) orally, intranasal calcitonin (Miacalcin),

etidro-in bone density if begun withetidro-in 3 yr of menopause Osteo- nate (Didronel), and slow-release fluoride also may be effective.

porosis risk increased in Caucasian and Asian ethnic (See Estradiol Notes.) groups, in sedentary lifestyle, in smokers, with low calcium

and vitamin D intake, and excessive alcohol or thyroxine intake.

Fractures One-half as many fractures of spinal and hip bones with >5 yr Bone densitometry can identify women at highest risk.

of use; 28% reduction with 10 yr use; 40% with 15 yr use;

and 55% with 20 yr Risk returns near baseline 6 yr or more after cessation of therapy Decreased lifetime probability of osteoporotic fracture Risk increases 4-fold for each 1 SD decrease in bone density at the hip; 66% of femoral neck fractures occur when bone density is below the lowest quartile.

Vaginal Bleeding Unpredictable bleeding occurs in 35–40% of women with Amenorrhea usually occurs after 6–8 months of combination estrogen/

From references 119, 121, 127, 130, 132, 139, and 157–164.

Pharmacology Medroxyprogesterone is a 17-acetoxyprogesterone derivativewith greater progestational effects and oral efficacy than progesterone Proges-terone transforms an estrogen-primed proliferative endometrium into a secretoryendometrium.

Administration and Adult Dosage PO for secondary amenorrhea, or mal uterine bleeding, or to induce withdrawal bleeding after postmenopausal estrogen replacement therapy 5–10 mg/day for 5–10 days, depending on the de-

abnor-gree of endometrial stimulation desired, beginning on the presumed 16th or 21stday of the cycle for abnormal uterine bleeding In secondary amenorrhea, therapy

can be started at any time PO for postmenopausal symptoms and osteoporosis

(combined with continuous estrogen) 2.5–5 mg/day.140,141(See Notes.) PO for

re-lief of vasomotor symptoms 20 mg/day; IM for rere-lief of vasomotor symptoms

150 mg/day.142(See Notes.) IM for endometrial or renal carcinoma 400 mg–

1 g/week initially for a few weeks, then, if improvement occurs, reduce to

mainte-nance dosage of 400 mg/month (See also Progestin-Only Contraceptives.)

Special Populations Geriatric Dosage Same as adult dosage.

Dosage Forms Tab 2.5, 5, 10 mg; Inj 150, 400 mg/mL.

Patient Instructions Report immediately if any of the following occur: new

se-vere or persistent headache; blurred vision; calf, chest, or abdominal pain; or anyabnormal vaginal bleeding This (oral) drug may be taken with food, milk, or anantacid to minimize stomach upset (Dysfunctional uterine bleeding) expect heavyand severely cramping flow 2–4 days after stopping therapy; expect a normal pe-riod after a few days

Pharmacokinetics Onset and Duration Withdrawal bleeding (in estrogen-primed

endometrium) occurs 3–7 days after the last dose.103,104Onset of symptomatic lief of hot flashes within 4–7 days; maximum relief after 1 month; duration 8–20weeks after discontinuation.142

re-Serum Levels Inhibition of ovulation and tumor response occurs with

medroxy-progesterone levels >0.1 g/L (0.25 nmol/L).101,103,104,143

Fate Medroxyprogesterone acetate (MPA) is rapidly absorbed orally with no

first-pass metabolism; oral bioavailability is 5.7 ± 3.8%; IM bioavailability is2.5 ± 1.7%, with a large interpatient variation in serum levels after oral or IM ad-ministration.82,143Higher concentration depot formulation is associated with lowerserum concentrations but equivalent bioavailability.144Peak concentrations occur

in 2–7 hr and are 2–10 times higher after oral than after IM depot injection PO 10

mg yields peak levels of 3–4 g/L (7.5–10 nmol/L), declining to 0.3–0.6 g/L(0.8–1.5 nmol/L) by 24 hr; PO 100 mg yields 13 ± 7 g/L (34 ± 18 nmol/L),declining to 2 g/L (5 nmol/L) by 24 hr; PO 500 mg yields 13 ± 8 g/L (34 ± 21 nmol/L) After 150 mg IM of the 150 mg/mL formulation, peak levels of8.3 ± 3.2g/L (21 ± 8 nmol/L) occur within a few days, declining to levels of0.8 ± 0.7 g/L (2 ± 1.8 nmol/L) for 92 ± 44 days After 400 mg IM of the

400 mg/mL formulation, peak serum levels of 6.2 ± 2.3 g/L (16 ± 6 nmol/L) areachieved after 16.3 ± 15.6 days.82,94,103,104,144The drug is stored in fat; >90% is

MEDROXYPROGESTERONE ACETATE Depo-Provera, Provera, Various

protein bound to albumin; 83% of a dose is present in serum as the parent drugand conjugated medroxyprogesterone; it is hydroxylated to 6--hydroxy-MPAand 21-hydroxy-MPA, which have unknown activities From 15% to 20% of adose is excreted in urine as glucuronide and sulfate conjugates; 45–80% is ex-creted in feces.94

t¹⁄₂ 50 days, reflecting slow IM absorption from depot.

Adverse Reactions Frequent breast tenderness, weight gain, and depression

occur Adverse lipid effects (increased LDL, decreased HDL) occur with dosages

≥10 mg/day; dosages of 2.5–5 mg/day have negligible effects.121,140,144(See also

Progestin-Only Contraceptives, Postmenopausal Hormone Replacement Risksand Benefits Comparison Chart, and Hormone Excess and Deficiency Symptoma-tology Comparison Chart.)

Contraindications Known or suspected pregnancy or as a diagnostic test for

pregnancy Thrombophlebitis, history of deep vein thrombophlebitis, or boembolic disorders; known or suspected carcinoma of the breast or en-dometrium, or other estrogen-dependent tumors; undiagnosed abnormal genitalbleeding Although acute liver disease, benign or malignant liver tumors, and his-tory of cholestatic jaundice of pregnancy or jaundice with prior hormonal contra-ceptive use are listed as contraindications by manufacturers, liver disease is notconsidered by others to be a contraindication to progestin-only contraceptives.96

throm-Precautions Use with caution in patients with histories of depression, diabetes,

gestational diabetes, coronary artery disease, cerebrovascular disease, demia, liver disease, or hypertension Although progestins are not harmful to thefetus during the first 4 months of pregnancy; confirm a negative pregnancy testbefore reinjecting a woman >2 weeks late for her IM injection.96,105Progestin-only contraceptives used during breastfeeding pose no risk to the infant,96,103–107

hyperlipi-and they usually do not decrease breastmilk production if begun after 6 weekspostpartum

Drug Interactions Rifampin and cytochrome P450–inducing anticonvulsants can

increase progestin metabolism Long-term use of griseofulvin can increase strual irregularities.76,96,103,104,108

men-Parameters to Monitor Complete pretreatment physical examination with

spe-cial reference to blood pressure, breasts, abdomen, pelvic organs, and Pap smearyearly

Notes Continuous administration of low-dose progestin and estrogen

combina-tions in postmenopausal syndrome causes amenorrhea in >50% of women anddoes not appear to negatively influence blood lipids when compared with cyclictherapy.121,140,141,145 Concurrent administration of estrogen with progestin foramenorrhea might be associated with less breakthrough bleeding than with pro-gestin alone There is no evidence that progestins are effective in preventing habit-ual abortion or treating threatened abortion

Pharmacology Mifepristone (RU-486) is a synthetic steroid with

antiprogesta-tional effects

Adult Dosage PO for pregnancy termination through day 49 of pregnancy

600 mg as a single dose, followed in 2 days by misoprostol 200 mg PO Patientsshould return on day 14 to assess efficacy of the procedure and bleeding

Dosage Forms Tab 200 mg.

Pharmacokinetics Oral bioavailability is 69% with a 20 mg dose It is 98%

bound to albumin and 1-acid glycoprotein It is metabolized primarily byCYP3A4 to three major metabolites Most of drug is eliminated in feces, with 9%

of the drug and metabolites eliminated in urine Clearance is dose dependent, with50% eliminated between 12 and 72 hr; the remaining drug is eliminated with ahalf-life of 18 hr

Adverse Reactions Vaginal bleeding and cramping are expected effects of the

drug (plus misoprostol) and occur mostly on day 3 Bleeding is generally heavierthan a normal menstrual period Other frequent effects are nausea, vomiting, diar-rhea, headache, dizziness, and fatigue Drugs that affect CYP3A4 can altermifepristone metabolism The metabolism of drugs metabolized by CYP3A4might be affected

Contraindications Confirmed or suspected ectopic pregnancy or undiagnosed

abdominal mass; IUD in place; chronic adrenal failure; concurrent long-term ticosteroid use; allergy to mifepristone, misoprostol or other prostaglandin; hem-orrhagic disorder; anticoagulant therapy; inherited porphyria

cor-Notes Pregnancy termination should be conducted only in a setting where a

qual-ified physician can assess the gestational age of the fetus, diagnose ectopic nancies, and provide surgical intervention in case of incomplete abortion or severebleeding (or have made plans to provide such care through others)

preg-Pharmacology Norethindrone acetate is a 19-nortestosterone derivative that

shares the actions of progestins It has oral efficacy, greater progestational activity

than progesterone, and less androgenic activity than androgens (See also

Medroxyprogesterone Acetate, Progesterone.)

Administration and Adult Dosage PO for withdrawal bleeding after menopausal estrogen replacement therapy or combined for estrogen replace- ment therapy 2.5–10 mg/day starting on days 15–20 of the cycle and continuing

post-for 5–10 days, or 0.5–1 mg/day continuously combined with estrogen.140,141,145

(See Medroxyprogesterone Acetate Notes.) PO for amenorrhea or abnormal

uterine bleeding 2.5–10 mg/day starting on day 5 and ending on day 25 of

menses In cases of secondary amenorrhea, therapy can be started at any time.79

PO for endometriosis 5 mg/day for 2 weeks, increasing in 2.5 mg/day increments

q 2 weeks until a maintenance dosage of 15 mg/day is reached.80

Special Populations Geriatric Dosage Same as adult dosage.

Dosage Forms Tab 5 mg.

Patient Instructions Report immediately if any of the following occur: new

se-vere or persistent headache; blurred vision; calf, chest, or abdominal pain; or anyabnormal vaginal bleeding This (oral) drug may be taken with food, milk, or an

antacid to minimize stomach upset (Dysfunctional uterine bleeding) expect heavyand severely cramping flow 2 to 4 days after stopping therapy; expect a normalperiod after a few days.

Pharmacokinetics Onset and Duration (Uterine bleeding) after oral

administra-tion, acute bleeding should decrease in 1–2 days and stop in 3–4 days drawal bleeding) onset 3–7 days after last oral dose.81

(With-Fate Norethindrone acetate is rapidly and completely absorbed, with a mean

bioavailability of 64 ± 16% because of first-pass metabolism.81–85,94drone acetate is rapidly converted to norethindrone in vivo.81,85,87,90Norethindrone

Norethin-is 36% bound to sex hormone-binding globulin and 61% bound to albumin It Norethin-isconcentrated in body fat and endometrium; breast milk levels are 10% of maternalserum levels Vdis 4.3 ± 9 L/kg; Cl is 0.5 ± 1.5 L/hr/kg Over 50% is eliminated inurine and 20–40% in feces as conjugated glucuronides and sulfates; <5% ofnorethindrone acetate is excreted as unchanged norethindrone.81–85,90,94

t¹⁄₂ (Norethindrone) 6.4 ± 3 hr.81–85,90,94

Adverse Reactions (See Medroxyprogesterone Acetate, Postmenopausal

Hor-mone Replacement Risks and Benefits Comparison Chart, and HorHor-mone Excessand Deficiency Symptomatology Comparison Chart.)

Contraindications (See Medroxyprogesterone Acetate, Postmenopausal

Hor-mone Replacement Risks and Benefits Comparison Chart.)

Precautions (See Medroxyprogesterone Acetate, Postmenopausal Hormone

Re-placement Risks and Benefits Comparison Chart, and Hormone Excess and ciency Symptomatology Comparison Chart.)

Defi-Drug Interactions, Parameters to Monitor, Notes (See Medroxyprogesterone

Acetate.)

Pharmacology Progesterone is the natural hormone that induces secretory

changes in the endometrium, relaxes uterine smooth muscle, and maintains nancy Hydroxyprogesterone is a natural progestin with minimal progestationalactivity; esterification with caproic acid produces a progestational compoundmore potent than progesterone with a prolonged duration of activity

preg-Administration and Adult Dosage PO to prevent endometrial hyperplasia during postmenopausal estrogen replacement therapy (micronized proges-

terone) 200 mg/day for 12 days of cycle.118IM for secondary amenorrhea or dysfunctional uterine bleeding (progesterone) 5–10 mg/day for 6–8 days or

(only for amenorrhea) 100–150 mg as a single dose; (hydroxyprogesterone

caproate) 375 mg, may repeat in 4 weeks prn IM for palliation of metastatic

en-dometrial cancer (hydroxyprogesterone caproate) 500 mg–1 g 2–3 times/week Intrauterine for contraception (progesterone) 38 mg q 12 months, releases

68g/day; insert at any time during menstrual cycle or within 7 days of onset ofmenses, immediately postabortion, or no earlier than 6 weeks postpartum if

PROGESTERONE Crinone, Progestasert, Prometrium, Various

HYDROXYPROGESTERONE CAPROATE Duralutin, Various

breastfeeding; insertion and removal are done by trained personnel Vag for

pro-gesterone supplementation (propro-gesterone) 90 mg daily (See Notes.)

Special Populations Geriatric Dosage Same as adult dosage.

Dosage Forms Cap (micronized progesterone) 100, 200 mg (Prometrium); Inj

(progesterone in oil) 50 mg/mL; (hydroxyprogesterone caproate in oil) 125,

250 mg/mL; Intrauterine (progesterone) 38 mg (Progestasert); Vag Gel

(pro-gesterone 8%) 90 mg/applicatorful (Crinone)

Patient Instructions Report immediately if any of the following occur: new

se-vere or persistent headache; blurred vision; calf, chest, or abdominal pain; or anyabnormal vaginal bleeding (Dysfunctional uterine bleeding) expect heavy flowand severe cramping 2 to 4 days after injection; expect a normal period after a fewdays (Progestasert only) you might experience increased menstrual flow, cramp-ing, and spotting Check the position of the strings monthly after each period orafter abnormal cramping to ensure proper placement of the IUD Contact yourprescriber immediately if the strings are missing, if you miss a menstrual period,

or if you have fever, pelvic pain, severe cramping, unusual vaginal bleeding, orany signs of infection

Pharmacokinetics Onset and Duration (Amenorrhea) onset of withdrawal

bleed-ing occurs 48–72 hr after last dose of IM progesterone and 2 weeks after IM droxyprogesterone caproate; (dysfunctional uterine bleeding) onset within 6 days

hy-of IM progesterone.79Duration is 12–24 hr with oral progesterone, 9–17 days with

IM hydroxyprogesterone caproate (Contraception) onset within 24 hr after tion of Progestasert

inser-Serum Levels (Endometrial progestational activity [luteal phase]) 15 g/L (48 nmol/L) of progesterone

Fate (Progesterone) bioavailability of oral progesterone is incomplete because of

first-pass metabolism, with wide interpatient variations; micronized forms aresomewhat better absorbed.82,121,145,146 Higher levels of progesterone and activemetabolites occur after IM, vaginal, or rectal administration because first-pass ef-fect is avoided Serum levels of progesterone after oral and IM increase rapidly toreach luteal-phase values within 2.4 ± 1.1 hr and remain elevated for <12 hr afteroral administration and 48 hr after IM administration (PO) 100 mg micronizedprogesterone yields peak progesterone levels of 7 ± 3.4 g/L (23 ± 11 nmol/L);

200 mg yields 28 ± 19 g/L (89 ± 59 nmol/L); (IM) 100 mg yields 60 g/L(192 nmol/L); (Vag) 200 mg bid yields 19 ± 2 g/L (61 ± 7 nmol/L); (Vag)

400 mg once daily yields 29 ± 53 g/L (93 ± 188 nmol/L).82,145,147Oral terone Vdis 850 ± 265 L/kg; Cl is 19 ± 38 L/hr/kg.145Progesterone circulates 80%bound to albumin and 17% to corticosteroid-binding globulin and distributes intofat It undergoes rapid gut and hepatic metabolism, with formation of activemetabolites: 20-dihydroprogesterone (25–50% of the progestational activity ofprogesterone), 17-hydroxyprogesterone, and 11-deoxycorticosterone (a potentmineralocorticoid).82,148,149 Hydroxyprogesterone caproate is cleaved to form 17-hydroxyprogesterone in the body; 17-hydroxyprogesterone, whether formedfrom progesterone or exogenously administered, is further metabolized to 11-deoxycortisol and then cortisol Urinary excretion of progesterone is 50–60%

as 5-pregnanediol glucuronide and other conjugated glucuronic acid or sulfatemetabolites; 5–10% excreted in feces.

t¹⁄₂ (Progesterone) 32.6 ± 9.3 hr.145

Adverse Reactions Local reactions and swelling at the site of progesterone

injec-tion The beneficial effects of estrogen-increased HDL levels are not reversed byprogesterone.121(See Postmenopausal Hormone Replacement Risks and Benefits

Comparison Chart, Hormone Excess and Deficiency Symptomatology son Chart.) (Progestasert) intermenstrual spotting and menstrual bleeding irregu-larities, expulsion, ectopic pregnancy, uterine perforation, pelvic inflammatorydisease, cramping, and pain Intrauterine administration of contraceptive doses ofprogesterone has no systemic effects.76

Compari-Contraindications (See Medroxyprogesterone Acetate.) Progestasert

preg-nancy; active, recent, or recurrent pelvic infections, including gonorrhea or

Chlamydia infection.

Precautions (See Medroxyprogesterone Acetate, Postmenopausal Hormone

Re-placement Risks and Benefits Comparison Chart, and Hormone Excess and ciency Symptomatology Comparison Chart.) Patients allergic to peanuts shouldnot use Prometrium

Defi-Drug Interactions (See Medroxyprogesterone Acetate.)

Parameters to Monitor Complete pretreatment and annual physical

examina-tions with special reference to blood pressure, breasts, abdomen, pelvic organs,and Pap smear

Notes Progesterone is widely used in the treatment of premenstrual syndrome;

however, in double-blind, controlled trials, oral micronized and vaginal terone were no better than placebo.150,151

proges-Pharmacology Raloxifene is a selective estrogen receptor modulator similar to

tamoxifen It acts like an estrogen in the bone and like an estrogen antagonist onthe breast and uterus Raloxifene increases bone mineral density and decreasesserum LDL cholesterol levels but does not stimulate endometrial growth.152,153

Administration and Adult Dosage PO for prevention of postmenopausal teoporosis 60 mg once daily with supplemental calcium.

os-Dosage Forms Tab 60 mg.

Pharmacokinetics Oral bioavailability is 2% because of an extensive first-pass

effect It is highly bound to albumin and 1-acid glycoprotein and has a Vdof

2348 L/kg Cl is 40–60 L/hr/kg The drug is metabolized to glucuronide lites, some of which undergo enterohepatic recycling, and can be converted back

metabo-to the parent drug Metabolites are excreted primarily in feces The half-life isabout 28 hr

Adverse Reactions Hot flashes occur in 25–30% of women; leg cramps also are

frequent It increases the risk of venous thrombosis and is a teratogen

Contraindications Women who might become pregnant or who have a history of

venous thrombotic events

Drug Interactions Cholestyramine (and presumably colestipol) binds raloxifene

and reduces its absorption and enterohepatic recirculation The drugs should not

be coadministered Raloxifene decreases the effect of warfarin, and PT should bemonitored carefully when they are given together

Notes Raloxifene increases bone mineral density, decreases the risk of vertebral

fracture,154and decreases the risk of invasive breast cancer.155It also favorably ters cardiovascular risk factors (eg, LDL-c, lipoprotein-a, HDL-c), but protectionagainst cardiovascular disease is not established.156

al-Thyroid and Antithyroid Drugs

Pharmacology Iodide inhibits the synthesis and release of thyroid hormone and

preoperatively decreases the size and vascularity of the hyperplastic thyroid gland.Large doses block the uptake of radioactive iodine by the thyroid gland

Administration and Adult Dosage PO for hyperthyroidism, as an adjunct to antithyroid agents or for preoperative thyroidectomy preparation 100–

200 mg (5 drops of saturated solution of potassium iodide [SSKI] or 10–15 drops

of Lugol’s solution) q 8 hr diluted in a glass of water, milk or juice; dosages as high

as 500 mg/day have been used However, administration of smaller doses of30–50 mg iodine and continued suppression with doses of 15–50 mg/day also may

be effective in patients with mild disease.165Use for 7–10 days before surgery PO

for thyroid storm 200 mg q 6 hr PO for prophylaxis in radiation emergency

100 mg iodine immediately before or within 1–2 hr after exposure and daily for3–7 days, to a maximum of 10 days after exposure

Special Populations Pediatric Dosage PO for thyrotoxicosis 300 mg (6 drops

SSKI) q 8 hr diluted as above PO for prophylaxis in a radiation emergency

(<1 yr) 50 mg iodine immediately before or after exposure and daily for 3–7 days,

to a maximum of 10 days after exposure; (>1 yr) same as adult dosage

Geriatric Dosage Same as adult dosage.

Dosage Forms Soln (SSKI) 50 mg/drop iodide (1 g/mL); (Lugol’s or strong

io-dine) 8 mg/drop iodide (50 mg/mL iodine plus 100 mg/mL potassium iodide);

Tab 100 mg iodide (130 mg potassium iodide); EC Tab not recommended Patient Instructions Dilute solution in a glass (8 fluid ounces) of liquid before

taking; it may be taken with food, milk, or an antacid to minimize stomach upset

Do not use if solution turns brownish-yellow If crystals form in the solution, theycan be dissolved by warming the closed container in warm water Dissolve tablets

in one-half glass of water or milk before taking Do not use if you are ing; advise your physician if you are pregnant Discontinue use and report if fever,skin rash, epigastric pain, or joint swelling occur

breastfeed-Pharmacokinetics Onset and Duration Onset 24–48 hr in hyperthyroidism;

max-imum effect in 10–15 days (See Notes.)

Serum Levels (Iodide) >50 g/L (0.4 mmol/L) inhibits iodide binding by thyroid

in hyperthyroidism; >200 g/L (1.6 mmol/L) inhibit iodide uptake by normal roid.166

Fate Iodide is well absorbed throughout the GI tract and concentrated in the

thy-roid, stomach, salivary glands, and breastmilk Renal clearance is 1.8 L/hr/kg; proximately 100 g of iodine is excreted in urine daily; fecal excretion of iodine

ap-is negligible.166

Adverse Reactions Any adverse reaction warrants drug discontinuation Goiter,

hypothyroidism, and hyperthyroidism occur frequently in euthyroid patients with

a history of a thyroid disorder.167–171Iodism occurs with prolonged use and is cated by metallic taste, GI upset, soreness of teeth and gums, coryza, frontalheadaches, painful swelling of salivary glands, diarrhea, acneiform skin eruptions,and erythema of face and chest Rarely, hypersensitivity occurs and is manifested

indi-by angioedema, cutaneous hemorrhages, and symptoms resembling serum

sick-ness (See Precautions.)

Contraindications Pulmonary tuberculosis; pulmonary edema; multinodular

goi-ters.165,167–170

Precautions Pregnancy, because fetal goiter, asphyxiation, and death can occur;

lactation Use iodides with caution in patients with untreated Hashimoto’s roiditis, in iodide-deficient patients, in children with cystic fibrosis, and in euthy-roid patients with histories of postpartum thyroiditis, subacute thyroiditis, amio-darone or lithium-induced thyroid disease, or previously treated Graves’ diseasebecause they can be particularly sensitive to iodide-induced hypothyroidism.167–171

tPatients with nontoxic multinodular goiters might be prone to development of perthyroidism Avoid iodides entirely in patients with toxic nodular goiter or toxicnodules because thyrotoxicosis can be further aggravated.165,167–170Iodides are notrecommended for use as expectorants because of their potential to induce ac-neiform eruptions, exacerbate existing lesions, and adversely affect the thyroid.Small-bowel lesions are associated with enteric-coated potassium-containingtablets, which can cause obstruction, hemorrhage, perforation, and possible death.This dosage form is not recommended

hy-Drug Interactions Iodide prevents uptake of 131I for several weeks and delaysonset of thioamide action if given before the thioamide Lithium can potentiate theantithyroid action of iodide Serum iodine can be elevated if potassium-sparing di-uretics are taken with potassium iodide

Parameters to Monitor Monitor for signs of iodism (see Adverse Reactions),

hy-pothyroidism, hyperthyroidism, and parotitis occasionally during long-term use.Monitor thyroid function tests at least q 6–12 months during long-term use in pa-tients with family histories of thyroid disease or goiter Monitor serum potassiumfrequently in patients who are taking other drugs that might affect serum potas-sium (eg, diuretics)

Notes Iodide has the most rapid onset of any treatment for hyperthyroidism In

thyroid storm, iodide theoretically should be given 1 hr after the thioamide dosebut should not be withheld if oral thioamides cannot be given The therapeutic ef-

fects of iodide are variable and transient, with “escape” occurring after 10–14days; do not use iodide alone in the therapy of hyperthyroidism.165Pharmacologic

amounts of iodide can be present in serum from radiographic contrast agents and vaginal douches such as povidone-iodine.167–170

Pharmacology Levothyroxine is a synthetic hormone identical to the thyroid

hormone T4 Thyroid hormones are responsible for normal growth, development,and energy metabolism

Administration and Adult Dosage PO for replacement in hypothyroidism

<6 months duration full replacement dosage of 1.6–1.7 g/kg/day initially, ing if needed and tolerated in 25–50 g/day increments at 6–8 week intervals to amaintenance dosage that normalizes thyroid-stimulating hormone (TSH).172–174

increas-Usual maintenance dosages 75–100 g/day for women and 100–150 g/day formen Higher mean replacement dosages are required in patients with spontaneoushypothyroidism (1.7–1.8 g/kg/day) than in those with iatrogenic hypothyroidismafter radioiodine therapy for Graves’ disease (1.5–1.6 g/kg/day).172–175Once-weekly replacement therapy can be effective.176PO for replacement of subclinical hypothyroidism same as adult dosage The desirability of treatment is con-

troversial; benefits are greatest in those with TSH >10 IU/mL, lesterolemia, and subtle symptoms of hypothyroidism Replacement reduces lev-els of homocysteine and may lower the risk of clinical cardiovascular disease (eg,

hypercho-MI, aortic atherosclerosis.)177–179 PO for suppression therapy of nodules

100–150 g/day initially, increasing, if necessary and tolerated, in 25–50 g/dayincrements at 6–8 week intervals to suppress TSH to below normal, detectablelimits to prevent further thyroid growth Dosages are usually higher than thoserequired for replacement therapy and risks must be assessed, especially in patientswith cardiac disease If no improvement after 1 yr, consider stopping ther-apy.180,181PO for suppression therapy of thyroid cancer after thyroidectomy

2.11 g/kg/day initially, increasing, if needed and tolerated, in 25–50 g/day crements at 6–8 week intervals to a dosage of 150–250 g/day to suppress theTSH level to undetectable levels.172–175IV for myxedema coma 400–500 g or

in-300 g/m2to increase serum T4 levels by 3–5 g/dL (39–65 nmol/L), then50–100 g/day until oral administration is possible; use smaller dosages in cardio-vascular disease.182,183IM indicated only for replacement therapy if the patient

cannot take oral medication; parenteral dosage is about 80% of the oral dosage cause of bioavailability differences.172,173

be-Special Populations Pediatric Dosage PO for hypothyroidism (preterm infants

and full-term neonates to 1 yr) 10–15 g/kg/day to normalize T4to >10 g/dL(129 nmol/L) within 3–4 weeks; (>1 yr) 3–5 g/kg/day (average 3.5).172,184Adjustmaintenance dosage on the basis of growth, development, and T4and TSH values.Replacement by at least 24 months of age corrects short stature by age 5 yr Syrupcan be formulated from tablets, with a stability of 15 days.185

Geriatric Dosage PO for hypothyroidism (>50 yr) start with 25–50 g/day tially, then increase if tolerated in 12.2–25 g/day increments at 6–8 week inter-

ini-LEVOTHYROXINE SODIUM Levothroid, Levoxyl, Synthroid, Unithroid, Various

vals to a maintenance dosage necessary to normalize TSH; (>65 yr) <1 g/kg/daymay be required.172–175IV for myxedema coma (>55 yr) <500 g initially to im-prove outcome, then same as adult dosage.182Poorly compliant elderly patients(mean age 86 yr) have been maintained on a twice-weekly dosing regimen; how-ever, this regimen might be dangerous in cardiac patients.186

Other Conditions In patients with cardiovascular disease or severe, long-standing

(>6 months) myxedema, PO 12.5–25 g/day initially, increasing, if tolerated, at6–8 week intervals by 12.5–25 g/day increments to a maintenance dosage neces-sary to normalize TSH.172–175In patients with cardiovascular disease, particularlyangina, dosage increments should be balanced between exacerbation of anginaand maintenance of euthyroidism In some patients with severe coronary disease,incomplete control of hypothyroidism might be necessary to prevent further exac-erbation of angina During pregnancy, a 20–50% increase in dosage might be re-quired to maintain a normal TSH level.172–175In those with continued mood distur-bances on sole T4therapy, see Liothyronine.

Dosage Forms Tab 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, 300 g;

Inj 200, 500 g

Patient Instructions This medication must be taken regularly to maintain proper

hormone levels in the body Report immediately if chest pain (especially in derly patients), palpitations, sweating, nervousness, or other signs of overactivityoccur

el-Missed Doses Take any missed dose as soon as it is remembered, but if more than

1 dose is missed, do not double dosage

Pharmacokinetics Onset and Duration PO onset 3–5 days; peak effect 3–4

weeks; duration after cessation of therapy 7–10 days IV onset in myxedema coma6–8 hr, maximum effect in 1 day.172,182,183

Serum Levels (Physiologic and therapeutic during levothyroxine therapy) free T4

6–21 ng/L (12–26 pmol/L); total T450–120 g/L (65–155 nmol/L) Peak free

T4levels can be 12.7 ± 2.6%, and total T4levels 8.l ± 1.2% higher than trough els or levels obtained 10 hr after a dose.187,188Many drugs and pathologic andphysiologic states affect binding and hence can affect results of some serum leveldeterminations.166,167,169,171,174

lev-Fate Oral bioavailability ranges from 74 ± 11% to 93 ± 25% and can be creased by many factors (eg, malabsorption, concurrent food, and drugs; see Drug

de-Interactions).167,189A dose of 500 g IV increases serum T4levels by 3–5 g/dL(39–65 nmol/L).172,183Only 0.03% is unbound in plasma Vdis (hypothyroid)0.17 ± 0.22 L/kg; (euthyroid) 0.16 ± 0.09 L/kg; (hyperthyroid) 0.23 ± 0.44 L/kg.Turnover is (hypothyroid) 9.2 ± 1.7%/day; (euthyroid) 11.2 ± 1.7%/day; (hyper-thyroid) 21 ± 4.9%/day Cl is (hypothyroid) 0.0008 ± 0.0033 L/hr/kg; (euthyroid)0.00074 ± 0.0017 L/hr/kg; (hyperthyroid) 0.002 ± 0.0007 L/hr/kg.190About 80%

is deiodinated in the body; 35% is peripherally converted to the more active T3

and 45% to inactive reverse T3.166Another 15–20% is conjugated in the liver toform glucuronides and sulfates, which undergo enterohepatic recirculation withreabsorption or excretion in the feces

t¹⁄₂ (Hypothyroid) 7.5 ± 7.1 days; (euthyroid) 6.2 ± 4.7 days; (hyperthyroid) 3.2 ±

1.7 days.190Protein binding affects half-life (increased binding retards eliminationand decreased binding increases elimination)

Adverse Reactions Most are dose related and can be avoided by increasing the

initial dosage slowly to the minimum effective maintenance dosage Signs ofoverdosage are headache, palpitations, chest pain, heat intolerance, sweating, legcramps, weight loss, diarrhea, vomiting, nervousness, and other symptoms of hy-perthyroidism Long-term thyroid administration that results in TSH suppressioncan predispose to ventricular hypertrophy, atrial fibrillation, osteoporosis, and in-creased fracture risk by increasing bone resorption in postmenopausal womenwith a history of hyperthyroidism.172–175,191

Contraindications Thyrotoxicosis; uncorrected adrenal insufficiency.

Precautions Initiate and increase dosage with caution in patients with

cardiovas-cular disease, the elderly, and in long-standing hypothyroidism In myxedemacoma, give a corticosteroid concurrently.183The status of other metabolic diseases,including diabetes, adrenal insufficiency, hyperadrenalism, and panhypopitu-itarism, can be affected by changes in thyroid status

Drug Interactions Bran, fiber, cholesterol-binding resins, sodium polystyrene

sulfonate, iron, aluminum-containing products, and calcium carbonate can crease oral absorption Phenytoin, carbamazepine, and other enzyme inducers;sertraline and possibly other serotonin reuptake inhibitors, and ritonavir can in-crease levothyroxine requirements.167,169,189,192 The action of some drugs (eg,digoxin, warfarin, insulin, sympathomimetics, theophylline) can be altered bychanging thyroid status.169,174

de-Parameters to Monitor (Adults) TSH, free T4or free T4index, and clinical tus of the patient q 6–8 weeks initially Monitor trough levels or obtain levels atleast 10 hr after tablet ingestion to avoid transient peak effects.187,188After stabil-ization, monitor free T4or free T4index, TSH, and clinical status at 6–12 monthintervals (Children) Monitor the parameters above q 4 weeks initially and q 3–4months after stabilization In congenital hypothyroidism, monitor T4because TSHcan remain elevated despite adequate replacement doses.184(>50 yr) Evaluate thereplacement dosage annually and adjust downward as necessary because dosagerequirements decrease with age.172–175

sta-Notes Levothyroxine is the drug of choice for thyroid replacement because of

purity, long half-life, and close simulation to normal physiologic hormone levels.Protect from light and moisture Concerns about tablet potency prompted the FDA

to require that all manufacturers submit a new drug application for levothyroxine

by August 2001 Unithroid is the first levothyroxine tablet to obtain FDA proval Bioequivalence is reported between Synthroid, Levothroid, and Le-voxyl.173,188,193Use of adjunctive thyroid hormones for depression may be effec-tive; T3is used instead of T4(see Liothyronine).194Physiologic dosages of thyroidhormones in euthyroid patients are ineffective for weight reduction, obesity, orpremenstrual tension; larger dosages might result in toxicity.175(See Thyroid Re-

ap-placement Products Comparison Chart.)

Pharmacology Liothyronine is a synthetic hormone identical to the thyroid

hor-mone T3, which is 4 times as potent by weight as T4 (See Levothyroxine.)

Administration and Adult Dosage PO for replacement in hypothyroidism <6 months in duration 25 g/day initially, increasing, if needed and tolerated, in12.5–25 g/day increments at 1–2 week intervals to a maintenance dosage of25–100 g/day to normalize TSH PO for severe hypothyroidism 5 g/day ini-

tially, increasing in 5–10 g/day increments at 1–2 week intervals until 25 g/day

is reached, then increase in 12.5–25 g/day increments at 1–2 week intervals untileuthyroid Dividing daily dosage into 2–3 doses can prevent wide serum level

fluctuations PO for augmentation of tricyclic therapy for depression 25–

50 g daily.194,195No data are available in combination with serotonin reuptake

inhibitors IV for myxedema coma 25–50 g initially, then 10–12.5 g q 4–6 hr

to a minimum of 10–15 g q 12 hr until PO administration is possible; use smallerdosages of 10–20 g IV initially in cardiovascular disease Some suggest that T3

is preferable in myxedema coma when impairment of T4to T3conversion is pected or in cardiac disease because adverse effects will dissipate faster.182,183

sus-Limited experience exists with IV dosages >100 g/day PO for T 3 suppression test 75–100 g/day in 2–3 divided doses for 7 days, then repeat 131I thyroid up-take test

Special Populations Pediatric Dosage PO for congenital hypothyroidism

5g/day initially, increasing in 5 g/day increments at 3–4 day intervals until the

desired effect is obtained Usual maintenance dosage (<1 yr) 20 g/day; (1–3 yr)

50 g/day; (>3 yr) 25–100 g/day Levothyroxine is the drug of choice in genital hypothyroidism.184

con-Geriatric Dosage Not recommended because of greater potential for cardiotoxicity.

PO if used, start at PO 5 g/day and increase in 5 g/day increments at 2-week

in-tervals, if tolerated, until desired response is obtained (See Levothyroxine.) Other Conditions Not recommended in those with cardiovascular disease but, if

used, start at PO 5 g/day and increase in 5 g/day increments at 2-week

inter-vals, if tolerated, until desired response is obtained (See Levothyroxine.) For

those with continued mood disturbances on sole T4therapy, substitution of T3

5g bid for 50 g of levothyroxine of the total daily T4replacement dosage hasbeen advocated.196

Dosage Forms Tab 5, 25, 50 g; Inj 10 g/mL.

Patient Instructions This medication must be taken regularly to maintain proper

hormone levels in the body Report immediately if chest pain (especially in derly patients), palpitations, sweating, nervousness, or other signs of overactivityoccur

el-Missed Doses Take any missed dose as soon as it is remembered, but if more than

1 dose is missed, do not double dosage

Pharmacokinetics Onset and Duration PO onset 1–3 days; duration after

cessa-tion of therapy 3–5 days

LIOTHYRONINE SODIUM Cytomel, Triostat, Various

Serum Levels During T3 replacement, T4 is maintained at ≤10 g/L (13 nmol/L).197

Fate Oral absorption is usually complete but can decrease in CHF With a typical

replacement dosage, T3has a peak of 4.5–7 g/L (7–11 nmol/L) 1–2 hr postdose,returning to 0.88–1.6 g/L (1.4–2.5 nmol/L) before the next dose 24 hr later.197Vd

is (hypothyroid) 0.53 ± 0.04 L/kg; (euthyroid) 0.52 ± 0.03 L/kg; (hyperthyroid)0.94 ± 0.07 L/kg Turnover is (hypothyroid) 50 ± 5%/day; (euthyroid) 68 ±11%/day; (hyperthyroid) 110 ± 22%/day Cl is (hypothyroid) 0.012 ± 0.002L/hr/kg; (euthyroid) 0.02 ± 0.003 L/hr/kg; (hyperthyroid) 0.043 ± 0.013L/hr/kg.190,198Excreted in urine as deiodinated metabolites and their conjugates

t¹⁄₂ (Hypothyroid) 38 ± 6 hr; (euthyroid) 25 ± 3 hr; (hyperthyroid) 17 ± 4.7 hr.190

Adverse Reactions (See Levothyroxine.) Dose-related adverse effects are more

likely and appear more rapidly than with levothyroxine because regulation ofdosage is more difficult Liothyronine and its mixtures (eg, desiccated thyroid, li-otrix) cause “unphysiologic” toxic peaks in serum T3levels not found duringlevothyroxine replacement therapy.172,174,175

Contraindications (See Levothyroxine)

Precautions (See Levothyroxine.)

Drug Interactions Normal serum T3levels are age related and can be decreased

by a wide variety of pharmacologic agents (eg, amiodarone, iodinated contrastdyes, corticosteroids, propylthiouracil) or clinical circumstances (eg, malnutrition,chronic renal, hepatic, pulmonary, or cardiac disease; or acute sepsis) which im-pair peripheral or pituitary T4to T3conversion.166,167,174(See also Levothyroxine

Drug Interactions.)

Parameters to Monitor Serum TSH and T3levels (See Levothyroxine.)

Notes Liothyronine is not considered the drug of choice for replacement therapy

in hypothyroidism because of its shorter half-life (necessitating more frequent ministration), greater potential for cardiotoxicity, the greater difficulty of monitor-ing, and its greater expense.172–174Liothyronine is the preparation of choice when

ad-thyroid supplements must be stopped before isotope scanning After scanning,

maintenance therapy with levothyroxine is recommended The use of IV T3aftercardiopulmonary bypass might improve postoperative recovery and cardiac func-tion in adults, children, and infants.199–201(See Thyroid Replacement Products

Comparison Chart.)

EQUIVALENT RELATIVE ONSET

Unithroid

Various

Liotrix Tab 1/4, 1/2, 1, 2, 3 b #1 Tab c T 4 and T 3 Intermediate No advantages; more costly and

Thyroid, Desiccated Tab 15, 30, 60, 90, 60 mg T 4 and T 3 Intermediate Inexpensive; allergy to animal

and T 3 toxicosis may occur.

a With equivalent dosages.

b Numbers represent equivalent dosage of thyroid in grains (ie, 15, 30, 60, 120, 180 mg, respectively).

c Thyrolar-1 contains T 4 50 µg and T 3 12.5 µg; other strengths are in the same proportion.

From references 172 –174.

Pharmacology Methimazole is a thioamide antithyroid drug that interferes with

the synthesis of thyroid hormones by inhibiting iodide organification Unlikepropylthiouracil (PTU), methimazole does not block peripheral conversion of T4

to T3 Titers of thyroid receptor–stimulating antibody (TRab) decline during apy, suggesting an immunosuppressive effect Methimazole is 10 times more po-tent than PTU on a weight basis

ther-Administration and Adult Dosage PO for hyperthyroidism 30–40 mg/day as a

single dose If GI intolerance occurs, divide dosage q 8 hr initially until euthyroid(usually 6–8 weeks), then decrease by 33–50% over several weeks to a mainte-nance dosage of 5–15 mg/day in a single dose Severe disease might require 2 di-vided doses The addition of levothyroxine is not recommended because remis-sion rates have not shown improvement.202 PO for thyroid storm 40–

120 mg/day, divided q 8 hr until euthyroid Traditional treatment duration for perthyroidism is 1–2 yr, although shorter courses of 8 months might be effective

hy-in mild disease.165Treatment may be continued indefinitely, if necessary, to

con-trol the disease and if no toxicity occurs PR methimazole can be formulated for

rectal administration.203

Special Populations Pediatric Dosage PO 0.5-0.7 mg/kg/day or 15–20

mg/m2/day, to a maximum of 30–60 mg/day given in 1–2 divided doses, with amaintenance dosage of 50% of the initial dosage.204

Geriatric Dosage Same as adult dosage.

Other Conditions In pregnancy, dosages should be as low as possible to maintain

maternal T4levels in approximately the upper normal to mildly thyrotoxic range.Initially give a maximum of 20–30 mg/day orally in single or 3 divided doses for4–6 weeks, then decrease to 5–15 mg/day in a single dose The intellectual devel-opment and growth of children exposed to methimazole in utero appear to be sim-ilar to unexposed siblings.205

Dosage Forms Tab 5, 10 mg.

Patient Instructions Report sore throat, fever, or oral lesions immediately

be-cause they might be early signs of a rare, but severe, blood disorder Also reportany skin rashes, itching, or yellowing of eyes and skin Be sure to take at pre-scribed dosage intervals

Missed Doses If you miss a dose, take it as soon as possible If it is time for the

next dose, take both doses

Pharmacokinetics Onset and Duration PO onset about 2–3 weeks, which is

con-sistent with the elimination of existing T4stores Duration intrathyroidally 40

hr.165,206

Serum Levels <0.2 mg/L (1.8 mol/L) inhibits iodide organification.206

Fate Well absorbed orally Considerable interindividual variations in

pharmaco-kinetic parameters Peak serum levels occur at 2.3 ± 0.8 hr; the peak after 30 mgorally is 0.8 ± 0.2 mg/L (6.8 ± 1.9 mol/L); after 60 mg orally, 1.5 ± 0.5 mg/L(14 ± 4 mol/L); after 60 mg rectally, 1.1 ± 0.5 mg/L (10 ± 5 mol/L).203,206,207

The drug is actively concentrated in the thyroid gland, with peak intrathyroidal

levels of 0.11–1.1 mg/L (1–10 mol/L) within 1 hr;206there is minimal plasmaprotein binding; it is distributed into breast milk 10 times greater than PTU.165Vd

is 1.4 ± 0.6 L/kg; Cl is 0.072 ± 0.018 L/hr/kg There are no active metabolites;7–12% is excreted unchanged in urine, 6% excreted as inorganic sulfate, 1.5% assulfur metabolites, and 50% as unknown metabolites.206,207

t¹⁄₂. phase 3 ± 1.4 hr;  phase 18.5 ± 13 hr in normal and hyperthyroid patients,increased to 21 hr in cirrhosis.206Intrathyroidal half-life is 20 hr

Adverse Reactions Maculopapular skin rashes and itching occur frequently and

can disappear spontaneously with continued treatment; urticaria requires drug continuation.165,175Methimazole can be given to patients who develop only anonurticarial maculopapular rash on PTU Mild transient leukopenia occurs fre-quently in untreated Graves’ disease, does not predispose to agranulocytosis, and

dis-is not an indication to ddis-iscontinue the drug.165,175Agranulocytosis occurs sionally, usually in the first 3 months of therapy Risk increases with dosages

occa->40 mg/day in patients occa->40 yr; granulocyte colony-stimulating factors (eg,

fil-grastim) can hasten recovery.165,175Rarely, fever, arthralgias, cholestatic or tocellular toxicity, vasculitis, lupus-like syndrome, hypoprothrombinemia, aplas-tic anemia, thrombocytopenia, nephrotic syndrome, loss of taste, and spontaneousappearance of circulating antibodies to insulin or glucagon occur.165,175,208Rareteratogenic risk of scalp defects.205

hepa-Contraindications Manufacturer states that breastfeeding is a contraindication,

but most experts feel that breastfeeding can be performed with dosages of ≤10mg/day and careful monitoring of infant thyroid function.165

Precautions Although methimazole crosses the placenta at rates 4 times greater

than propylthiouracil and has been associated with scalp defects (aplasia cutis),

recent reports indicate methimazole can be given in pregnant patients intolerant toPTU.165,205Use with caution during lactation and in patients with severe allergicreactions to other thioamides A low prevalence of cross-sensitivity occurs be-tween thioamide compounds for nonurticarial skin rashes, so if these occur, an-other thioamide can be substituted However, a 50% chance of cross-sensitivityexists for severe reactions (eg, agranulocytosis, hepatitis), so do not substitute an-other thioamide.165,175

Drug Interactions Iodide given before a thioamide delays the response to the

thioamide, especially in thyroid storm Changes in thyroid status can alter codynamics and pharmacokinetics of digoxin, warfarin, theophylline, -blockers,and insulin

pharma-Parameters to Monitor Monitor clinical status; serum free T4or T4index, andTSH monthly initially until euthyroid, then q 3–6 months Obtain occasional LFTsand CBC with differential (but these are not recommended routinely because theyare not predictive of toxicity, and transient leukopenia and elevations in LFTs canoccur) Obtain AST, ALT, total bilirubin, and alkaline phosphatase if patient re-ports signs of hepatitis; WBC and differential counts if patient reports signs ofagranulocytosis such as fever, sore throat, or malaise

Notes Methimazole is the drug of choice for treatment of uncomplicated

hyper-thyroidism because it is better tolerated and fewer tablets can be given once daily,

improving patient compliance.165Remission rates of 20–40% are common aftercessation of therapy Favorable remission rates correlate with longer duration oftherapy, higher dosages, mild disease, shrinkage of goiter size with therapy, disap-pearance of thyroid receptor–stimulating antibodies, and initial presentation with

T3toxicosis.165Most patients eventually require surgery or radioiodine; however,

a trial of a thioamide is worthwhile in patients with minimal thyroid enlargement

or very mild hyperthyroidism Adjunctive therapy with cholestyramine 4 g tid

can lower thyroid hormone levels more rapidly.209Methimazole rather than PTUmay be preferred during radioactive iodine therapy because it does not interferewith the thyroid uptake of iodine like PTU.210In thyroid storm, PTU is the drug ofchoice

Pharmacology Propylthiouracil (PTU) is a thioamide antithyroid drug that

blocks the synthesis of thyroid hormones and, at dosages >450 mg/day, decreasesthe peripheral conversion of T4to T3 Titers of thyroid receptor stimulating anti-body decline during therapy, consistent with an immunosuppressive effect

Administration and Adult Dosage PO for hyperthyroidism 100–200 mg

(de-pending on the severity of hyperthyroidism) q 6–8 hr initially until euthyroid ally 6–8 weeks), then decrease by 33–50% over several weeks to a maintenancedosage of 50–150 mg/day in a single dose Rarely, initial dosages of 1–1.2 g/day(maximum dosage) in 3–6 doses might be necessary.165PO for thyroid storm

(usu-200–250 mg q 6 hr until euthyroid; maintenance dosage is determined by patientresponse Traditional treatment duration for hyperthyroidism is 1–2 yr, althoughshorter courses of 8 months might be effective in mild disease.165,174Treatmentmay be continued indefinitely, if necessary, to control the disease and if no toxic-ity occurs The addition of levothyroxine is not recommended because remissionrates have not shown improvement.202PR PTU can be formulated for rectal ad-

ministration.211,212

Special Populations Pediatric Dosage Give orally in 3 divided doses PO

150–300 mg/m2/day Alternatively, (6–10 yr) 5–10 mg/kg/day or 50–150 mg/dayinitially; (≥10 yr) 150–300 mg/day initially.204Maintenance dosage is determined

by patient response

Geriatric Dosage Same as adult dosage.

Other Conditions In pregnancy, the dosage should be as small as possible to

main-tain a mildly hyperthyroid maternal state; initially 300 mg/day orally in 3 divideddoses for 4–6 weeks, then decrease to 50–150 mg/day in a single dose The intel-lectual development and growth of children exposed to PTU in utero appear to besimilar to unexposed siblings.205

Dosage Forms Tab 50 mg.

Patient Instructions Report sore throat, fever, or oral lesions immediately

be-cause they may be an early sign of a severe, but rare, blood disorder Also reportany skin rashes, itching, or yellowing of eyes and skin Be sure to take at pre-scribed dosage intervals

Missed Doses If you miss a dose, take it as soon as possible If it is time for the

next dose, take both doses

Pharmacokinetics Onset and Duration PO onset of therapeutic effect 2–3

weeks, consistent with the elimination of existing thyroxine stores

Serum Levels Peak PTU levels >4 mg/L (24 mol/L) produce antithyroid ity; 3 mg/L (18 mol/L) reduces organification by 50%; 0.8 mg/L (5 mol/L) re-duces peripheral conversion activity by 50%.207,213

activ-Fate Oral bioavailability is 77 ± 13% Peak levels occur 2 ± 0.3 hr after oral

ad-ministration and 4.7 ± 1 hr after rectal adad-ministration Peak serum level after anoral dose of 50 mg is 1 ± 0.2 mg/L (6 ± 1.2 mol/L); after 200 mg, 4.5 ± 0.7 mg/L(26 ± 4 mol/L); after 300 mg, 7 ± 0.8 mg/L (42 ± 5 mol/L); after 400 mg rec-tally, 3 ± 0.8 mg/L (18 ± 5 mol/L).211,212PTU is actively concentrated in the thy-roid gland, 40% as unknown metabolite, 32% as sulfate, and 20% as unchangedPTU; peak intrathyroidal levels of 0.17 ± 1.7 mg/L (1–10 mol/L) occur within

1 hr.207The drug is 80% plasma protein bound; it distributes poorly into breastmilk.165Vdis 0.29 ± 0.06 L/kg; Cl is 0.23 ± 0.04 L/hr/kg About 85% is excreted

in 24 hr, 61% as glucuronides, 8–9% as inorganic sulfates, 8–10% as unknownsulfur metabolites, and <10% excreted unchanged in urine.207,213

t¹⁄₂ 1.3 ± 0.6 hr.207,213

Adverse Reactions (See Methimazole.) Agranulocytosis is not more prevalent at

higher doses as it is with methimazole Rarely, hepatitis occurs; hepatocellulartoxicity is more frequent than cholestatic jaundice.165,175,214Transient transaminaseelevations can occur in asymptomatic individuals, which normalize within

3 months with continued drug administration

Contraindications Manufacturer states that breastfeeding is a contraindication,

but it can be used with infant thyroid monitoring because of low milk levels andlack of effect on infants.165,205

Precautions (See Methimazole.) Although it crosses the placenta poorly (25%

that of methimazole), it can cause fetal hypothyroidism and goiter.205Thyroid function can diminish as pregnancy progresses, allowing a reduction in dosage and,

dys-in some cases, a withdrawal of therapy 2–3 weeks before delivery Adjunctive roid hormone therapy prevents maternal hypothyroidism but, because of minimalplacental transfer, has little effect on the fetus.205Use with caution before surgery

thy-or during treatment with anticoagulants because of hypoprothrombinemic effect.175

Drug Interactions (See Methimazole.)

Parameters to Monitor (See Methimazole.) INR monitoring is advisable,

partic-ularly before surgery

Notes Because propylthiouracil decreases peripheral conversion of T4to T3, it isconsidered the thioamide of choice in treating thyroid storm Some prefer PTUrather than methimazole in pregnancy and breastfeeding, although either can beused.165,205Patients pretreated with PTU might require a 25% higher dosage of ra-dioactive iodine for efficacy.210

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Class Instructions Diuretics If you are taking more than one dose a day, take

the last dose in the afternoon or early evening to avoid having to void urine duringthe night Avoid heavily salted foods, but rigid salt restriction is not necessary.Avoid excessive water intake Report any dizziness or lightheadedness (especiallywhen arising from sitting or lying), muscle cramps, weakness, lethargy, drymouth, thirst, or low urine output

Missed Doses Take this drug at regular intervals If you miss a dose, take it as

soon as you remember If it is about time for the next dose, take that dose only Donot double the dose or take extra

Pharmacology Amiloride is a potassium-sparing diuretic with a mechanism and

site of action resembling triamterene It has mild antihypertensive activity and alonger duration of action than triamterene.1–3

Adult Dosage PO 10 mg/day in 1–2 doses, to a maximum of 20 mg/day,

al-though a dosage >10 mg/day is seldom necessary

Dosage Forms Tab 5 mg; Tab 5 mg with hydrochlorothiazide 50 mg (Moduretic

5-50, various)

Pharmacokinetics Onset within 2 hr; maximum effect 6–10 hr after an oral

dose; duration about 24 hr The drug is about 50% orally absorbed, decreasing to30% when taken with food Half the absorbed drug is excreted unchanged inurine Half-life is 6–9 hr in normal renal function, increasing up to 144 hr in renalfailure

Adverse Reactions Adverse reactions are generally similar to triamterene;

how-ever, in contrast to triamterene, renal stone formation has not been reported withamiloride

Pharmacology Bumetanide is a loop diuretic with renal pharmacology similar to

furosemide Bumetanide is estimated to be approximately 40 times as potent asfurosemide on a weight basis.1–6

Administration and Adult Dosage PO for diuresis 0.5–2 mg as a single dose

and repeat q 4–5 hr as needed, to a maximum of 10 mg/day IV or IM dose is

0.5–1 mg, IV given over 1–2 min Repeat doses may be administered as needed q2–3 hr, to a maximum of 10 mg/day For long-term control of edema, intermittent

Renal and Electrolytes

716

regimens are recommended as alternate daily doses or daily doses for 3–4 days

with 1–2 day drug holidays IV infusion 1 mg IV bolus, followed by (Clcr

>75 mL/min) 0.5 mg/hr; (Clcr25–75 mL/min) 0.5–1 mg/hr; or (Clcr<25 mL/min)1–2 mg/hr.3

Special Populations Pediatric Dosage 0.015–0.1 mg/kg/dose q 6–24 hr, to a

maximum of 10 mg/day

Geriatric Dosage Start with a low initial dose and titrate to response.

Other Conditions No adjustment is necessary for renal impairment, hemodialysis,

or chronic ambulatory peritoneal dialysis

Dosage Forms Tab 0.5, 1, 2 mg; Inj 0.25 mg/mL.

Patient Instructions (See Class Instructions: Diuretics.)

Pharmacokinetics Onset and Duration Onset is within 30–60 min after oral

ad-ministration and within minutes after IV adad-ministration Durations of diuresis are4–6 hr orally and 2–3 hr IV.5,6

Serum Levels Site of action is within the renal tubule and not the serum;

there-fore, serum concentrations do not reflect diuretic activity

Fate Bioavailability is 80–96%.5,6Vdssis 0.16–0.24 L/kg in normal subjects tein binding to albumin is 94–97% Renal excretion of unchanged drug accountsfor 50% of administered drug, with hepatic metabolism and biliary excretion ac-counting for the remainder The metabolites are inactive

Pro-t¹⁄₂ 0.3–1.5 hr; 1.9 ± 0.1 hr in renal insufficiency; 2.3 ± 0.4 hr in cirrhosis.5,6

Adverse Reactions Hypokalemia, hyponatremia, and hyperuricemia occur

fre-quently Muscle cramps, dizziness, hypotension, headache, and nausea occur casionally The ototoxic potential of bumetanide is believed to be less than that offurosemide and most likely associated with rapid IV administration, high-dosetherapy, or use in renal impairment

oc-Contraindications Anuria; hepatic coma; coexisting severe electrolyte depletion.

Precautions (See Furosemide.)

Drug Interactions Aminoglycoside-related ototoxicity risk can be increased with

concomitant bumetanide therapy Cardiac glycoside toxicity is enhanced with uretic-induced hypokalemia and hypomagnesemia Concomitant use with otherloop or thiazide diuretics enhances diuresis

di-Parameters to Monitor (See Furosemide.)

Pharmacology Furosemide is a loop diuretic that is actively secreted via the

non-specific organic acid transport system into the lumen of the thick ascending limb

of Henle’s loop, where it decreases sodium reabsorption by competing for thechloride site on the Na+-K+-2Cl−cotransporter.1,2Medullary hypertonicity is di-minished, thereby decreasing the kidney’s ability to reabsorb water Excretion ofsodium, chloride, potassium, hydrogen ion, calcium, magnesium, ammonium, bi-carbonate, and possibly phosphate is enhanced IV furosemide increases venous

capacitance independent of diuretic effect, producing rapid improvement in monary edema.1

pul-Administration and Adult Dosage PO for edema 20–80 mg as a single dose

ini-tially; double successive doses q 6–8 hr until response is obtained The maximumsingle oral dose depends on the disease state: 80 mg for hepatic cirrhosis with pre-served renal function,3240 mg for nephrotic syndrome,380–160 mg for CHF(with normal kidney function);3however, dosages up to 2500 mg/day have beenrecommended in refractory CHF.7After response, effective dosage is given in1–3 doses daily; usual daily maintenance dosage depends on the single dose to

which the patient responded PO for chronic renal failure 80 mg initially,

in-creasing in 80 mg/day increments until response is obtained, to a maximum of

160 mg and 400 mg for Clcr<20 mL/min.8(See Special Populations.) PO for

hypertension 40 mg bid IV should be used only when oral administration is not

feasible IV doses may be given over 1–2 min, except the rate should not exceed

4 mg/min when large doses are given IM or IV for edema use one-half the dose

of PO furosemide (as outlined above);8may double the dose q 2 hr or more untildesired response is obtained This dosage is then given in 1–2 doses daily formaintenance Dosages up to 4 g/day IV have been used in refractory CHF.7IV for acute pulmonary edema 40 mg initially, may repeat in 30–60 min with 80 mg, if

necessary (assuming relatively normal kidney function) For patients with renalimpairment, the initial and subsequent doses must be adjusted based on renalfunction For example, if Clcris 50 mL/min (about one-half normal), the dosemust be doubled; if Clcris 25 mL/min, the dose must be quadrupled Continuous

IV infusion for edema 40 mg loading dose followed by (Clcr 75 mL/min)

10 mg/hr; (Clcr25–75 mL/min) 10–20 mg/hr; (Clcr<25 mL/min) 20–40 mg/hr.3

Special Populations Pediatric Dosage PO for edema 2 mg/kg in 1 dose

ini-tially, increasing by 1–2 mg/kg in 6–8 hr, if necessary, to a maximum of 6

mg/kg/day IM or IV 1 mg/kg in 1 dose initially, increasing by 1 mg/kg q 2 hr or

more until desired response is obtained, or to a maximum of 6 mg/kg/day

Maxi-mum single dose depends on renal function (See Notes.)

Geriatric Dosage Start with a low initial dose and titrate to response.

Other Conditions For Clcr<20 mL/min, maximal response is attained with single

IV doses of 200 mg (400 mg PO) Hence, there appears to be no need to ter larger single doses to such patients.8A diminished response can occur in se-vere decompensated CHF, caused in part by alterations in oral absorption9and de-creased renal blood flow (despite relatively normal GFR), resulting in decreaseddelivery of furosemide to the renal tubule; IV administration circumvents absorp-tion problems However, decompensated CHF usually affects only the rate ratherthan the extent of oral furosemide absorption.10In addition, high-dose therapymight be beneficial in severe, refractory CHF.9(See Administration and Adult

adminis-Dosage.) For patients with cirrhosis, dosage is based on renal function

Dosage Forms Soln 8, 10 mg/mL; Tab 20, 40, 80 mg; Inj 10 mg/mL.

Patient Instructions (See Class Instructions: Diuretics.)

Pharmacokinetics Onset and Duration (Venous capacitance) IV onset 5 min,

duration >1 hr (Diuresis) PO onset 30–60 min, peak 1–2 hr, duration 6 hr; IV

onset 15 min, peak 30–60 min, duration 1–2 hr; duration might be prolonged insevere renal impairment (Hypertension) maximum effect on BP might not occurfor several days.

Serum Levels Site of action is within the renal tubules and not the serum;

there-fore, serum concentrations do not reflect diuretic activity High serum levels can

be associated with ototoxicity.11

Fate Pharmacokinetics are variable and absorption is erratic; 61 ± 17% (range

20–100) is bioavailable in normals, 30–100% in renal failure.11,12The rate, but notthe extent, of absorption might be decreased in patients with edematous bowelcaused by decompensated CHF;1096–99% is plasma protein bound, reduced inCHF, renal disease, or cirrhosis.12Vdis 0.11 L/kg; Cl is 0.12 ± 0.24 L/hr/kg; Vd

and Cl depend on protein binding.11,12Two possible inactive metabolites exist: aglucuronide, which is excreted primarily in urine (and to a lesser extent in thefeces by passive diffusion into the GI lumen), and saluamine, which could be atrue metabolite or an analytical artifact Renal clearance is primarily by active se-cretion; 50–80% (IV) and 20–55% (PO) are excreted unchanged in urine Renalclearance is decreased in renal failure, consistent with decreased renal blood flow,

a reduction of functioning nephrons, and the presence of competitive inhibitors forsecretion.12

t¹⁄₂ 92 ± 7 (range 30–120) min in normals, can be extended in cirrhosis to 81 ± 8

min or CHF to 122 min, and markedly prolonged in end-stage renal disease to 9.7

hr, and in multiorgan failure to 20–24 hr Mean residence time has been proposed

as a more appropriate estimate of duration: 51.4 min (IV); 135–195 min (PO).11,12

Adverse Reactions Dehydration, hypotension, hypochloremic alkalosis, and

hy-pokalemia are frequent Hyperglycemia and glucose intolerance occur as with

thi-azides (See Hydrochlorothiazide.) With high-dose therapy (>250 mg/day),

hyper-uricemia occurs frequently Tinnitus and hearing loss, occasionally permanent,occur frequently in association with rapid IV injection of large doses in patientswith renal impairment.8,12,13 Rarely, thrombocytopenia, neutropenia, jaundice,pancreatitis, and a variety of skin reactions occur

Contraindications Anuria (except for single dose in acute anuria).

Precautions Use with caution in patients with severe or progressive renal

dis-ease; discontinue if renal function worsens Use with caution in liver disease (canprecipitate hepatic encephalopathy), history of diabetes mellitus or gout, and inpatients allergic to other sulfonamide derivatives Use with caution in patientswith hypokalemia, hypomagnesemia, or hypocalcemia

Drug Interactions Cholestyramine and colestipol decrease furosemide

absorp-tion, and NSAIDs can decrease the diuretic effect of furosemide Aminoglycosideototoxicity can be enhanced in renally impaired patients IV furosemide can pro-duce flushing, sweating, and BP variations in patients taking chloral hydrate

Parameters to Monitor Monitor serum potassium closely, other electrolytes

pe-riodically, and serum glucose, uric acid, BUN, and Crsoccasionally Observe forclinical signs of fluid or electrolyte depletion such as dry mouth, thirst, weakness,lethargy, muscle pains or cramps, hypotension, oliguria, tachycardia, and GIupset

Notes Furosemide is light sensitive; oral solution should be stored at 15–30°Cand protected from light In severe proteinuria (>3.5 g/day), urinary albumin bindsfurosemide and reduces its effectiveness, explaining the higher dosage required toachieve adequate free drug concentrations.10In general, clinical nonresponderstend to have a decreased fraction of loop diuretics excreted in the urine For thesepatients and those with CHF and renal impairment, larger doses may force moredrug into the tubule; however, the risk of ototoxicity must be considered Alterna-

tively, combined use with a thiazide or metolazone orally can be effective by

blocking sodium reabsorption at multiple tubule sites; however, these agents pecially metolazone) have a slow onset of action Alternative treatment regimens

(es-include IV acetazolamide and low-dose dopamine given with the loop

di-uretic.4,7,14(See Loop Diuretics Comparison Chart.)

DRUG FORMS DOSAGE a DOSAGE a RENAL IMPAIRMENT COMMENTS

Bumetanide Tab 0.5, 1, 2 mg PO for edema 0.5–2 mg/ PO, IM, or IV 0.01– For Cl cr <15 mL/min, 1 mg PO or IV = 40 mg IV

Bumex Inj 0.25 mg/mL day, to a maximum of 0.02 mg/kg, to a maximal response is at- furosemide.

IM or IV over 1–2 min or 10 mg total IV doses of 8–10 mg;

0.5–1 mg, to a max- daily dosage IV infusion of 12 mg

Ethacrynic Tab 25, 50 mg PO minimal dose in the PO (infants) not established; Not recommended with Cl cr Nonsulfonamide Reliable

Acid Inj 50 mg range of 50–200 mg/ (children) 25 mg or 1 mg/ <10 mL/min; for Cl cr of potency data not

avail-Edecrin day initially, to a max- kg initially, increased in 10–50 mL/min, increase able; however, 50 mg

imum of 200 mg bid 25 mg increments to de- interval to q 8–12 hr IV is about equal to

fu-IV 50 mg or 0.5–1 mg/ sired effect; IV not es- rosemide 35 mg IV.

kg, to a maximum of tablished; 1 mg/kg has

Furosemide Tab 20, 40, 80 mg (See monograph.) (See monograph.) Maximum response occurs IV dose averages 50% of

although quite variable.

Torsemide Tab 5, 10, 20, (See monograph.) (See monograph.) Maximal response occurs 5–10 mg PO or IV = 20

a Higher doses needed for patients with CHF, liver cirrhosis, and nephrotic syndrome.

Pharmacology Thiazides increase sodium and chloride excretion by interfering

with their reabsorption in the cortical diluting segment of the nephron; a mild uresis of slightly concentrated urine results.1,2Excretion of potassium, bicarbon-ate, magnesium, phosphate, and iodide excretion is increased; calcium excretion isdecreased Decreases in interstitial fluid volume, reductions in intracellular cal-cium secondary to a fall in smooth muscle sodium concentration, and a change inthe affinity of cell surface receptors to vasoconstrictive hormones are thought to

di-be among the mechanisms for the hypotensive effect of the thiazides Urine output

is paradoxically decreased in diabetes insipidus.1

Administration and Adult Dosage PO for edema 25–200 mg/day in 1–3 doses

initially; 25–100 mg/day or intermittently for maintenance, to a maximum of

200 mg/day PO for hypertension 12.5–50 mg/day Maintenance dosages

>50 mg/day provide little additional benefit in controlling essential hypertensionand can increase the frequency of dose-related biochemical abnormalities.15

Special Populations Pediatric Dosage PO (<6 months) up to 3.3 mg/kg/day in

2 divided doses; (>6 months) 2–2.2 mg/kg/day in 2 divided doses

Geriatric Dosage Start with a low initial dose and titrate to response.

Other Conditions At a Clcr<30 mL/min, usual dosages of thiazides and most lated drugs are not very effective as diuretics but may be used in conjunction withloop diuretics.16

re-Dosage Forms Tab 25, 50, 100 mg; Cap 12.5 mg; Soln 10 mg/mL.

Patient Instructions (See Class Instructions: Diuretics.) If stomach upset occurs,

take drug with meals Report persistent anorexia, nausea, or vomiting

Pharmacokinetics Onset and Duration Onset of diuresis within 2 hr; peak in 4–6

hr; duration 6–12 hr Onset of hypotensive effect in 3–4 days; duration ≤1 weekafter discontinuing therapy

Serum Levels The site of diuretic action is within the renal tubules and not the

serum; therefore, serum concentrations do not reflect diuretic activity

Fate Oral bioavailability is 71 ± 15% in healthy individuals, increased when

given with an anticholinergic, and decreased by one-half in CHF and after nal shunt surgery There are no differences in absorption among single-entity for-mulations The drug is 58 ± 17% plasma protein bound; Vdis 0.83 ± 0.31 L/kg; Cl

intesti-is 0.29 ± 0.07 L/hr/kg Over 95% intesti-is excreted unchanged in urine by filtration andsecretion In severe renal impairment, renal clearance is prolonged 5-fold, withnonrenal clearance (mechanism as yet unidentified) playing a larger role in elimi-nation.11,17

t¹⁄₂ 2.5 ± 0.2 hr; prolonged in uncompensated CHF or renal impairment.11,17,18

Adverse Reactions Hypokalemia is frequent; however, its treatment in otherwise

healthy hypertensive patients is usually unnecessary Potassium supplements or

potassium-sparing diuretics (see Notes) may be indicated in patients with

arrhyth-mias, MI, or severe ischemic heart disease; those with chronic liver disease; derly eating poor diets; patients taking digoxin, a corticosteroid, or drugs that in-

el-HYDROCHLOROTHIAZIDE Esidrix, HydroDIURIL, Oretic, Various

terfere with ventricular repolarization such as phenothiazines and heterocyclic tidepressants; and those whose serum potassium level fall below 3 mEq/L Hyper-uricemia occurs frequently but is reversible, and treatment is unnecessary unlessthe patient has renal impairment or a history of gout.19Hyperglycemia and alter-ations in glucose tolerance (usually reversible), loss of diabetic control, or precipi-tation of diabetes mellitus occur occasionally Decreased glucose tolerance mightincrease in prevalence after several years of therapy.20,21Thrombocytopenia andpancreatitis occur rarely Elevation of serum cholesterol and triglycerides occurs;the clinical importance is unknown but can increase the risk of coronary heart dis-ease.

an-Contraindications Anuria; pregnancy, unless accompanied by severe edema;

al-lergy to sulfonamide derivatives

Precautions Use with caution in patients with renal function impairment, liver

disease (can precipitate hepatic encephalopathy), history of diabetes mellitus, orgout Use with caution in patients with diabetes mellitus because thiazides mightworsen glucose intolerance.20,21

Drug Interactions Cholestyramine and colestipol decrease oral absorption of

thi-azides, and NSAIDs can decrease the diuretic effect of thiazides Anticholinergicscan increase oral bioavailability Dosage of potent hypotensive agents might have

to be reduced if a thiazide is added to the regimen Concurrent calcium-containingantacids can cause hypercalcemia Long-term thiazides can reduce lithium excre-tion

Parameters to Monitor Monitor serum potassium weekly to monthly initially; q

3–6 months when stable Monitor other serum electrolytes periodically Monitorall electrolytes more closely when other losses occur (eg, vomiting, diarrhea) Ob-serve for clinical signs of fluid or electrolyte depletion such as dry mouth, thirst,weakness, lethargy, muscle pains or cramps, hypotension, oliguria, tachycardia,and GI upset Monitor BP periodically during antihypertensive therapy and serumglucose in patients with diabetes mellitus

Notes For the prevention of hypokalemia during thiazide therapy, a sparing diuretic may be preferred over potassium supplements in alkalotic pa-

potassium-tients because these agents decrease hydrogen ion loss, which can correct sis and drive more potassium extracellularly.22Potassium-sparing diuretics alsomay be preferred for patients predisposed to hypomagnesemia and for those withserum potassium <3 mEq/L because potassium supplements rarely correct hy-

alkalo-pokalemia of this severity (See Thiazides and Related Diuretics Comparison

Chart.) JNC-VI guidelines recommend diuretics and -blockers as initial drugs ofchoice for patients with hypertension based on demonstrated reductions in mor-bidity and mortality

ORAL DIURETIC EQUIVALENT PEAK DURATION

ORAL DIURETIC EQUIVALENT PEAK DURATION

Aquatensen

Enduron

Various

a From USP-DI and product informtion; patients unresponsive to maximal dosage of one agent are unlikely to respond to another agent.

b Dosages are for edema.

c There is no therapeutic advantage in giving the drug parenterally.

d Not a thiazide, but similar in structure and mechanism of action.

e Thalitone and Mykrox are more bioavailable than other formulations of the respective drugs.

Pharmacology Mannitol and other osmotic diuretics do not act on specific

recep-tors but rather on tubular fluid composition after filtration at the glomerulus nitol inhibits sodium and chloride reabsorption in the proximal tubule and ascend-ing loop of Henle predominantly Excretion of sodium, potassium, calcium, andphosphate is increased Renal blood flow is increased, the GFR of superficialnephrons is increased, and that of deep nephrons is decreased.23Mannitol in-creases serum osmolality by expanding intravascular volume and decreasing in-traocular and intracranial pressures.1,3,23

Man-Administration and Adult Dosage Never administer IM or SC or add to whole

blood for transfusion IV as diagnostic evaluation of acute oliguria (if BP and

CVP are normal and after cardiac output is maximized) give test dose of 12.5 g as

a 15–20% solution over 3–5 min (often given with furosemide 80–120 mg IV),

may repeat in 1 hr if urine output is <50 mL/hr If no response after 2 doses, give

no more mannitol and treat for acute tubular necrosis If response occurs, look for

underlying cause of oliguria (eg, hypovolemia) IV for prevention of acute renal

failure give test dose as above to a total dose of ≥50 g in 1 hr as a loading dose,then maintain urine output at 50 mL/hr with continuous infusion of 5% solution,

plus 20 mEq/L sodium chloride and 1 g/L calcium gluconate IV for reduction of

intracranial or intraocular pressure 1.5–2 g/kg over 30–60 min as a 15–20%

solution IV to decrease nephrotoxicity of cisplatin 12.5 g IV push just before

cisplatin, then 10 g/hr for 6 hr as a 20% solution Replace fluids with 0.45%sodium chloride with 20–30 mEq/L potassium chloride at 250 mL/hr for 6 hr.Maintain urine output >100 mL/hr with mannitol infusion.24,25(See Notes.)

Special Populations Pediatric Dosage IV for oliguria or anuria give test dose

of 20 mg/kg as above; the therapeutic dose is 2 g/kg over 2–6 hr as a 15–20%

so-lution IV for reduction of intracranial or intraocular pressure 2 g/kg over 30–60 min as a 15–25% solution IV for intoxications 2 g/kg as 5–10% solution

as needed to maintain a high urinary output (See Notes.)

Geriatric Dosage Start with a low initial dose and titrate to response.

Dosage Forms Inj 5, 10, 15, 20, 25%.

Pharmacokinetics Onset and Duration (Diuresis) onset 1–3 hr, duration depends

on half-life (Decrease in intraocular pressure) onset in 30–60 min, duration 4–6

hr (Decrease in intracranial pressure) onset within 15 min, peak 60–90 min, tion 3–8 hr after stopping infusion.26

dura-Serum Levels The site of diuretic action is within the renal tubules and not the

serum; therefore, serum concentrations do not reflect diuretic activity

Fate About 17% is absorbed orally IV doses of 1 and 2 g/kg increase serum

os-molality by 11 and 32 mOsm/kg, decrease serum sodium by 8.7 and 20.7 mEq/L,and decrease hemoglobin by 2.2 and 2.5 g/dL, respectively.27Vcis 0.074 L/kg;

Vdis 0.23 L/kg; Cl is 0.086 L/hr/kg.28Mannitol is eliminated almost completelyunchanged in urine

t¹⁄₂. phase 0.11 ± 0.12 hr;  phase 2.2 ± 1.3 hr.28